Engineering of the methylmalonyl-CoA metabolite node of Saccharopolyspora erythraea for increased erythromycin production

Reeves, Andrew R.; Brikun, Igor A.; Cernota, William H.; Leach, Benjamin I.; Gonzalez, Melissa C.; Weber, Jesse N.

doi:10.1016/j.ymben.2007.02.001

Cited by 89 publications

(59 citation statements)

References 38 publications

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“…151 Recently, engineering S. erythraea through duplication of the methylmalonyl-CoA mutase led to a 50% increase in erythromycin production. 152 Moreover, glucose or glycerol inhibits S-adenosylmethionine erythromycin O-methyl transferase activity. Reeve and Baumberg 153 measured the effect of glucose on the transcription of the eryAI gene, encoding the type I polyketide synthase.…”

Section: Streptomycesmentioning

confidence: 99%

Carbon source regulation of antibiotic production

et al. 2010

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Section: Streptomycesmentioning

confidence: 99%

Carbon source regulation of antibiotic production

et al. 2010

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“…Although tedious and time-consuming, the strategy can increase titers 10-to 100-fold (1). In rational engineering, knowledge of biochemical pathways guides genetic manipulations to increase titers, such as through modification of the methylmalonyl-CoA metabolite node (2). Often, overexpression of a gene that regulates the biosynthetic cluster of an antibiotic increases titers.…”

mentioning

confidence: 99%

A key developmental regulator controls the synthesis of the antibiotic erythromycin in Saccharopolyspora erythraea

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Vroom

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Saccharopolyspora erythraea makes erythromycin, an antibiotic commonly used in human medicine. Unusually, the erythromycin biosynthetic (ery) cluster lacks a pathway-specific regulatory gene. We isolated a transcriptional regulator of the ery biosynthetic genes from S. erythraea and found that this protein appears to directly link morphological changes caused by impending starvation to the synthesis of a molecule that kills other bacteria, i.e., erythromycin. DNA binding assays, liquid and affinity chromatography, MALDI-MS analysis, and de novo sequencing identified this protein (M r ‫؍‬ 18 kDa) as the S. erythraea ortholog of BldD, a key regulator of development in Streptomyces coelicolor. Recombinant S. erythraea BldD bound to all five regions containing promoters in the ery cluster as well as to its own promoter, the latter with an order-of-magnitude stronger than to the ery promoters. Deletion of bldD in S. erythraea decreased the erythromycin titer in a liquid culture 7-fold and blocked differentiation on a solid medium. Moreover, an industrial strain of S. erythraea with a higher titer of erythromycin expressed more BldD than a wild-type strain during erythromycin synthesis. Together, these results suggest that BldD concurrently regulates the synthesis of erythromycin and morphological differentiation. The ery genes are the first direct targets of a BldD ortholog to be identified that are positively regulated.cell differentiation ͉ secondary metabolites ͉ BldD

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“…Previous studies have shown that antibiotics production can be enhanced by increasing precursors. [24][25][26] In this study,one metabolic distinction among the three strains was a remarkable accumulation of acetyl-CoA in WH124 during the middle stage of the fermentation process (Fig. 4c).…”

Section: Discussionmentioning

confidence: 61%